Chronic myeloid leukemia: Relevance of cytogenetic and molecular assays

Bennour, Ayda; Sarkhosh, Ali; Sennana, Halima

doi:10.1016/j.critrevonc.2015.08.020

Cited by 37 publications

(17 citation statements)

References 89 publications

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“…The resultant constitutively active tyrosine kinase, Bcr-Abl, mediates phosphorylation and activation of downstream signaling pathways, causing altered cell adhesion, inhibition of apoptosis, differentiation arrest, and proteasomal degradation of key proteins, which lead to the phenotype of the disease (1). CML is considered to be one of the cancers most sensitive to immunological manipulation (2).…”

Section: Introductionmentioning

confidence: 99%

Immune Effector Recovery in Chronic Myeloid Leukemia and Treatment-Free Remission

2017

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Chronic myeloid leukemia (CML) is a hematological cancer, characterized by a reciprocal chromosomal translocation between chromosomes 9 and 22 [t(9;22)], producing the Bcr-Abl oncogene. Tyrosine kinase inhibitors (TKIs) represent the standard of care for CML patients and exert a dual mode of action: direct oncokinase inhibition and restoration of effector-mediated immune surveillance, which is rendered dysfunctional in CML patients at diagnosis, prior to TKI therapy. TKIs such as imatinib, and more potent second-generation nilotinib and dasatinib induce a high rate of deep molecular response (DMR, BCR-ABL1 ≤ 0.01%) in CML patients. As a result, the more recent goal of therapy in CML treatment is to induce a durable DMR as a prelude to successful treatment-free remission (TFR), which occurs in approximately half of all CML patients who cease TKI therapy. The lack of overt relapse in such patients has been attributed to immunological control of CML. In this review, we discuss an immunological timeline to successful TFR, focusing on the immunology of CML during TKI treatment; an initial period of immune suppression, limiting antitumor immune effector responses in newly diagnosed CML patients, linked to an expansion of immature myeloid-derived suppressor cells and regulatory T cells and aberrant expression of immune checkpoint signaling pathways, including programmed death-1/programmed death ligand-1. Commencement of TKI treatment is associated with immune system re-activation and restoration of effector-mediated [natural killer (NK) cell and T cell] immune surveillance in CML patients, albeit with differing frequencies in concert with differing levels of molecular response achieved on TKI. DMR is associated with maximal restoration of immune recovery in CML patients on TKI. Current data suggest a net balance between both the effector and suppressor arms of the immune system, at a minimum involving mature, cytotoxic CD56dim NK cells may be important in mediating TFR success. However, a major goal remains in CML to identify the most effective pathways to target to maximize an advantageous immune response and promote TFR success.

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Section: Introductionmentioning

confidence: 99%

Immune Effector Recovery in Chronic Myeloid Leukemia and Treatment-Free Remission

2017

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“…It should be remembered that both variant and secondary translocations may be a result of sub-microscopic changes, which are invisible in classical karyotype analysis. In this situation, it is important to use cytogenetic molecular techniques, such as fluorescence in situ hybridisation (FISH) [15,16]. At present, ELN guidelines promote more detailed tests for patients with an increased cytogenetic risk, but they do not clearly indicate that physicians should diversify initial therapies in everyday practice [6].…”

Section: Discussionmentioning

confidence: 99%

Złożona translokacja wariantowa t(9;22;6;17;1) w przebiegu leczenia przypadku przewlekłej białaczki szpikowej.

Chudy¹,

Pieńkowska-Grela²,

Kotyl³

et al. 2020

Nowotwory. Journal of Oncology

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The presence of the Philadelphia chromosome (Ph) in chronic myelogenous leukaemia (CML) is a specific cytogenetic change resulting from a reciprocal translocation between chromosomes 9 and 22. In 5-10% of newly diagnosed cases there are variant translocations (vPh) involving more chromosomes. This paper presents the case of a CML patient with a complex variant translocation involving chromosomes 1, 6, 9, 17 and 22. A molecular analysis did not reveal any mutation in the kinase domain of BCR-ABL1 gene or the mutation of TP53 gene. After the first-line treatment with imatinib no cytogenetic or molecular response was obtained. The change of treatment to dasatinib resulted in a minimal cytogenetic response (minCyR) followed by a minor cytogenetic response (mCyR). The application of nilotinib in the third-line treatment resulted in a complete molecular response (CMolR) and therapy success. The likely reason for the failure of the first-and second-line treatment was the loss of a fragment of the 17p13 region as a result of a variant translocation. The change can be a functional equivalent of the loss of one copy of TP53. The analysis of presented case confirms the significance of the detailed evaluation of the composition of vPh complex variant translocations as well as importance of combination cytogenetic and molecular diagnostics in CML treatment monitoring. It makes possible to adequate diagnose higher-risk patients and apply effective treatment strategies if an aberration is identified.

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“…Variant translocations may be caused by different mechanisms. Some variants are originated by multiple simultaneous breaks (one-step) and some arise as a result of two, or even more, genetic events in close succession (two-step or multiple-step) (9)(10)(11). In our series, the complex variant t(9;22;V) was identified in 30 out of 32 cases at the time of diagnosis suggesting that the t(9;22;V) originated in a stem cell, probably as the result of a one-step translocation.…”

Section: Discussionmentioning

confidence: 99%

Conventional and molecular cytogenetic studies to characterize 2 complex variant Philadelphia translocations in patients with chronic myeloid leukemia

et al. 2019

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BCR/ABL1 gene fusion is the hallmark of chronic myeloid leukemia (CML), and is generated in 5-10% of patients by a variant translocation involving 9q34, 22q11.2 and one or more additional genomic regions. The objective of the present study was to characterize, by conventional and molecular cytogenetics, 32 complex variant Philadelphia (Ph) translocations present at diagnosis in patients with CML. The chromosomes most frequently involved were 1 and 5, and the breakpoint most frequently involved was 12p13. The q-chromosome arm was more frequently involved (60%) than the p-arm. The breakpoints were located in the G-light bands in the majority of cases (85%). Additional chromosomal abnormalities were observed in 6 out of 32 (19%) patients. In conclusion, the combination of conventional and molecular cytogenetics studies has allowed us to: i) Detect and quantify the BCR/ABL1 fusion gene; ii) characterize the complex variant translocations and detect cryptic translocations; iii) confirm that the breakpoints are commonly localized in the G-light bands; (iv) confirm that the genesis of variant translocations could be via either the one-step or two-step mechanisms; and v) to report new cases of complex variant translocations.

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Chronic myeloid leukemia: Relevance of cytogenetic and molecular assays

Cited by 37 publications

References 89 publications

Immune Effector Recovery in Chronic Myeloid Leukemia and Treatment-Free Remission

Immune Effector Recovery in Chronic Myeloid Leukemia and Treatment-Free Remission

Złożona translokacja wariantowa t(9;22;6;17;1) w przebiegu leczenia przypadku przewlekłej białaczki szpikowej.

Conventional and molecular cytogenetic studies to characterize 2 complex variant Philadelphia translocations in patients with chronic myeloid leukemia

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